This report includes work arising from the following clinical protocols: NCT00030147, NCT00060736, NCT00001231, and NCT00001322. In addition to the well-documented increased risk of depression, the perimenopause also has been reported to be accompanied by a decreased quality of life (QOL). Studies have not clarified if the decline in QOL is secondary to the vicissitudes on the perimenopause (including distressing hot flushes) or if these changes in QOL reflect the effects of those women with perimenopausal depression (PMD). We have characterized the impact of PMD on QOL, disability, social adjustment and role functioning. Our findings show that PMD is accompanied by a decreased QOL, decreased social adjustment and impaired role functioning comparable to depression and anxiety disorders occurring at other stages of a womans life. Hot flushes did not significantly impact on these measures in either women with PMD or controls. These findings suggest that previous community-based reports of decreased QOL measures in perimenopausal women likely reflects the effects of the subgroup of perimenopausal women experiencing depression. The nature of the relationship between the onset of PMD and hormonal events of the perimenopause remains to be more fully characterized. Observational studies report the emergence of depressive symptoms after the discontinuation of estradiol therapy (ET) in 5-10% of women. The role of estradiol -either declining or low levels - in the precipitation of PMD is unknown, largely due to the associational and indirect nature of the evidence linking ovarian function and depression. Prospective epidemiological studies cannot test the estradiol withdrawal hypothesis since perimenopausal changes in the secretion of several hormonal and metabolic factors could confound the effects of estradiol withdrawal. In other studies of the role of ovarian steroids in affective disturbance, changes in ovarian steroids (in the context of otherwise normal levels) have been shown to directly trigger depression, but only in a subset of women with histories of mood disorders linked to reproductive function. We determined if sudden, blinded withdrawal of ET would precipitate depressive symptoms and if it would do so differentially in those with a history of PMD. Our findings support both predictions. Estradiol withdrawal precipitated depression in women with a history of PMD, but depressive symptoms emerged in neither women with no past history of PMD after estradiol withdrawal, nor in those women with past PMD who were maintained on ET. Importantly, the recurrence of depressive symptoms in women with past PMD occurred in the absence of differences in several measures that could influence mood, including baseline clinical characteristics (other than PMD), the severity of daytime/nighttime hot-flushes, and plasma hormone levels after withdrawal. The lack of depressive symptoms in the control women despite identical hormone manipulation (and similar levels of hot-flushes and plasma estradiol levels) demonstrates that estradiol withdrawal differentially impacts CNS function in some women so as to render them susceptible to depression. These observations, in the context of similar plasma reproductive hormone levels, suggest that normal changes in ovarian estradiol secretion can trigger an abnormal behavioral state in susceptible women. There are several mechanisms by which changes in estradiol might mediate the observed effects on mood. Estradiol and its receptors modulate the activity of virtually every system implicated in the pathogenesis of depression, including regulation of neurotransmitter synthesis and metabolism, stress axis activation, neuroplasticity (including regulation of BDNF), epigenesis, and immune system activation. Indeed, estradiol signaling through estrogen receptor (ER) beta reverses depressive-like behavior in animal studies. We intend to initiate a protocol examining the role of ER beta in estradiol-withdrawal-induced mood symptoms. What remains unclear is the reason for the differential susceptibility to the mood destabilizing effects of estradiol withdrawal. Of interest in this regard is the recent identification of increased sensitivity to estrogen regulation among transcripts that were differentially expressed in women who developed postpartum depression. Thus we have begun experiments employing lymphoblastoid and induced pluripotent cells from women with past PMD and controls to examine the molecular basis of the differential sensitivity to estradiol withdrawal. One possible source of the susceptibility to developing perimenopausal depression is an abnormal hypothalamic pituitary-adrenal (HPA) axis. Dysfunction of the HPA axis is a frequent accompaniment of depression, and HPA axis function is modulated by both aging and ovarian steroid secretion. We examined HPA axis function in depressed and asymptomatic perimenopausal women using the combined dexamethasone-corticotropin releasing hormone test. Results demonstrate that abnormalities of HPA axis function do not distinguish women with PMD from control women. These findings suggest that reproductive endocrine-related mood disorders are not uniformly associated with the HPA dysregulation and could reflect underlying pathophysiologic processes that are distinct from those reported in women with non-reproductive-related depressions.